This application addresses broad Challenge Area 15 (Translational Science), and the Specific Challenge Topic 15-AA-101: Determining If and How Adolescent Behaviors Affect Connections in the Developing Brain. Adolescence is a developmental period associated with non-linear changes in affective and social behavior, and a rapid rise in the risk of onset for a number of psychiatric disorders. Despite the large range in social and cognitive characteristics across mammalian species, many species show similar behavioral changes during the transition from the peri-pubertal period to adulthood. This apparent behavioral homology may reflect well-conserved neurodevelopmental processes that are specific to, or differently regulated in, adolescence. Despite the potential importance of such changes to psychiatric disorders, relatively few studies have directly examined neural circuit structure during adolescence. To address this, we recently completed a quantitative tract-tracing study, showing that in the rat, prefrontal cortical (PFC) inputs to the basal amygdala (BA) undergo pruning during the period analogous to late adolescence. The remodeling of PFC inputs to the BA, and possibly similar changes in temporal cortical inputs, may be important in the adaptive maturation of affective and social behavior. Conversely, disruptions of these neurodevelopmental processes may contribute to the emergence of neuro- and psychopathology in adolescence or young adulthood. These data make clear that the study of behavioral influences on adolescent brain circuitry must first take into account ongoing developmental processes that may be intrinsic to the neural circuit of interest. Herein, we postulate that, similar to the regulation of pruning in sensory cortical circuits earlier in development, pruning of prefrontal and temporal cortical inputs to the amygdala can be modified by experience. Given that adolescence in the rat (P25-P55;see Proposal for justification of age range) is associated with increased responsiveness to peers, we propose to test the hypothesis that during adolescence, social experience modulates the structural remodeling of cortico-amygdalar circuits. Thus, following characterization of remodeling in temporal cortical inputs to the BA, we will test whether during adolescence, pruning of PFC and temporo-limbic cortical inputs to the BA can be modified by social experience. Given that BA circuits are recruited by salient appetitive or aversive events, the social conditions will range from peer/play-enriched to isolation with threat. Beginning in young ("pre") adolescence (P24) rats will be housed in one the following conditions: with peers (which features vigorous play in adolescent rats), peer deprivation (housing with aged ovariectomized female), full social deprivation (single housing), or single housing with intermittent social threat (aggressive male). We will also test whether the effects of these social manipulations on cortico-amygdalar circuits are greater when experienced in adolescence relative to in adulthood. The differential effects of these social environments on cortico-amygdalar connectivity will be assessed with quantitative retrograde tracing methods. These studies will yield a more complete understanding of the structural and functional maturation of cortico-limbic circuits during adolescence. PUBLIC HEALTH RELEVANCE: During adolescence and young adulthood, the risk for many mental illnesses increases sharply. However, the neurodevelopmental changes that may underlie this increased vulnerability are not understood. The proposed studies will begin to bridge this important gap in our knowledge. Our findings will yield a more complete understanding of adolescence as a unique, sensitive period of development for brain circuits that mediate emotional regulation and social cognition. Moreover, the findings will contribute to the development of novel strategies for preventing the psycho- and neuropathology associated with many psychiatric disorders including schizophrenia, anxiety, and substance abuse disorders.